title: Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma.
abstract: OBJECTIVE
  To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single-agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity.
  
  
  METHODS
  This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose-escalation cohort followed by expansion cohort at maximum-tolerated dose. Exploratory analysis of serum cytokine levels was performed.
  
  
  RESULTS
  Thirty patients were enrolled onto four dose levels. The dose-limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%), and dyspnea (7%). A total of 10 patients (33%; indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n = 14), the overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymphoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, P = 0.013, and day 15, P = 0.021).
  
  
  CONCLUSIONS
  Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination.
authors.affiliation: Authors' Affiliations: Departments of Lymphoma/Myeloma, Diagnostic Imaging, and Biostatistics, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Oki
authors.forename: Daniela
authors.initials: D
authors.lastname: Buglio
authors.forename: Michelle
authors.initials: M
authors.lastname: Fanale
authors.forename: Luis
authors.initials: L
authors.lastname: Fayad
authors.forename: Amanda
authors.initials: A
authors.lastname: Copeland
authors.forename: Jorge
authors.initials: J
authors.lastname: Romaguera
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.forename: Barbara
authors.initials: B
authors.lastname: Pro
authors.forename: Silvana
authors.initials: S
authors.lastname: de Castro Faria
authors.forename: Sattva
authors.initials: S
authors.lastname: Neelapu
authors.forename: Nathan
authors.initials: N
authors.lastname: Fowler
authors.forename: Fredrick
authors.initials: F
authors.lastname: Hagemeister
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.forename: Shouhao
authors.initials: S
authors.lastname: Zhou
authors.forename: Lei
authors.initials: L
authors.lastname: Feng
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006689:Hodgkin Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D015848:Interleukin-5 / Q000097:blood; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000077767:Panobinostat; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D015848:Interleukin-5; D000077767:Panobinostat; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus